1. Field of the Invention
The invention relates to an EGFR-derived peptide useful for EGFR-based immunotherapy for cancer. In addition, the invention relates to a polypeptide comprising the EGFR-derived peptide capable of inducing both cellular and humoral immune responses and also a cancer vaccine containing said peptide.
2. Background of the Invention
Epithelial growth factor receptor (EGFR) plays an important role in epithelial biology and in many human malignancies (References 1-3). EGFR is a member of the receptor family comprising four, highly homologous proteins, HER2, HER3, and HER4 as well as EGFR. Those proteins in this family consist of an extracellular domain, a transmembrane domain, and an intracellular tyrosine kinase domain (Reference 20). Binding of the ligand such as epithelial growth factor (EGF) activates the intracellular tyrosine kinase domain to induce autophosphorylation of the receptor, which initiates the signaling cascade involved in cell proliferation and survival (Reference 20). The activation of EGFR highly involved in the processes of tumor proliferation and progression, including cell proliferation, inhibition of apoptosis, angiogenesis and metastasis (Reference 19). EGFR shows relatively high expression in approximately one-third of all types of epithelial cancers and the expression correlates with tumor progression, and therefore it is one of the most suitable targets in cancer therapy (References 21, 22).
As EGFR-targeted therapies, monoclonal antibodies which bind to the extracellular ligand binding site of the receptor and inhibitors for the intracellular tyrosine-kinase domain were intensively studied. Among them, a novel EGFR-tyrosine-kinase inhibitor ZD1839 is known to be effective for advanced non-small cell lung cancer (NSCLC) (References 4, 5).
It has been known that a living body has an immune system to eliminate tumor cells developed and that cytotoxic T lymphocyte (CTL) plays the central role in the system. CTL specifically recognizes an antigen presented on a tumor cell via a major histocompatibility complex (HLA in human) to kill the tumor cell. Taking advantage of the immune system for tumor cells, vaccine therapies, which include immunization of a body with epitope peptides of tumor antigens, have been attempted to potentiate the cytotoxicity against tumor cells.
Epitope peptides of HER2/neu, a member of the receptor family of EGFR, capable of inducing HLA-class I-restricted CTL were reported in the past decade (References 6-9). The inventers of the present invention previously reported that some CTL-directed peptides derived from non-mutated proliferation-related proteins had the ability to elicit both cellular and humoral immune responses in vivo in clinical studies (References 10-12). Further, levels of anti-peptide Abs in post-vaccination sera were well correlated with overall survival of advanced lung cancer patients who received peptide vaccination (Reference 12). In addition, there is a line of evidence for higher immunogenicity of a peptide capable of inducing both cellular and humoral immune responses (References 13-15), which can be expected to have more potent therapeutic activity.
The CTL epitope peptide of EGFR may be useful in cancer therapies in a different way from existing compounds, because it can be used as a peptide vaccine in EGFR-targeted therapies for cancer patients with tumors overexpressing EGFR. So far, however, there is no information about CTL epitopes of EGFR.